rs187003641

Variant names:

• chr4-15557482-G-A
• rs187003641
• NM_001378615.1:c.2804G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-15557482-G-A
• chr4-15557482-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378615.1(CC2D2A):​c.2804G>A​(p.Arg935Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000292 in 1,607,652 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (5 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 6.83
• Publications: 4 publications found

Genes affected

CC2D2A (HGNC:29253): (coiled-coil and C2 domain containing 2A) This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

CC2D2A Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 93

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007872403).
• BP6: Variant 4-15557482-G-A is Benign according to our data. Variant chr4-15557482-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126234.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00141 (214/152272) while in subpopulation AMR AF = 0.0134 (205/15286). AF 95% confidence interval is 0.0119. There are 5 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378615.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.2804G>A	p.Arg935Gln	missense	Exon 21 of 37	NP_001365544.1	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.2804G>A	p.Arg935Gln	missense	Exon 22 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.2657G>A	p.Arg886Gln	missense	Exon 19 of 35	NP_001365546.1	H0Y941

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.2804G>A	p.Arg935Gln	missense	Exon 21 of 37	ENSP00000403465.1	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.2804G>A	p.Arg935Gln	missense	Exon 22 of 38	ENSP00000421809.1	Q9P2K1-4
	CC2D2A	ENST00000634028.2	TSL:1	n.2657G>A		non_coding_transcript_exon	Exon 18 of 34	ENSP00000488669.2	A0A0J9YY35

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152154 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000573 AC: 136 AN: 237286 AF XY: 0.000598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000654

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000176 AC: 256 AN: 1455380 Hom.: 5 Cov.: 31 AF XY: 0.000181 AC XY: 131 AN XY: 723560

African (AFR) AF: 0.000150 AC: 5 AN: 33328

American (AMR) AF: 0.00449 AC: 197 AN: 43896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25852

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000388 AC: 43 AN: 1109126

Other (OTH) AF: 0.000150 AC: 9 AN: 60106

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152272 Hom.: 5 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74466

African (AFR) AF: 0.0000241 AC: 1 AN: 41560

American (AMR) AF: 0.0134 AC: 205 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.00131

ExAC AF: 0.000174 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CC2D2A-related disorder (1)
-	1	-	Joubert syndrome 9 (1)
-	1	-	Joubert syndrome 9;C2676790:Meckel syndrome, type 6;C5435651:COACH syndrome 1 (1)
-	1	-	Meckel syndrome, type 6 (1)
-	1	-	Meckel-Gruber syndrome (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0079	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.45
Sift	Benign	0.063	T
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.56
MVP		0.91
MPC		0.31
ClinPred		0.061	T
GERP RS		4.8
Varity_R		0.21
gMVP		0.41
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs187003641; hg19: chr4-15559105; COSMIC: COSV67502790; COSMIC: COSV67502790;